The objective of Drug Repurposing and Rediscovery for Gastrointestinal Stromal Tumors is to accelerate the development of new therapies for gastrointestinal stromal tumors (GIST) by employing a drug repurposing and rediscovery strategy. Upon its completion (within 12 months), this project will position the CTSA consortium to rapidly initiate a clinical proof of concept trial in GIST patients at multiple sites. The multidisciplinary, multi-organizational approach described in this application will demonstrate accelerated bench to bedside translation of new drug therapies for this rare cancer. The approach described represents a paradigm shift in drug repurposing and rediscovery from several perspectives: the proposed study i) capitalizes on cutting edge cancer biology research on GIST conducted at Johns Hopkins University and the University of Kansas; ii) employs a novel bioinformatics approach by integrating innovative CTSA bioinformatics capabilities located at Stanford University and Johns Hopkins University to generate in silico predictions of drug efficacy for those approved agents contained within the US Pharmacopeia; iii) utilizes unique, fully validated in vitro and in vivo preclinical proof of concept models available at the Universit of Kansas to determine preclinical proof of concept for single as well as combination GIST drug treatment; and iv) benefits from experiences and expertise gained from several repurposing and rediscovery focused drug development programs, each of which have targeted rare and neglected diseases. This initiative will significantly impact patients who suffer from GIST. Potential drug therapies will be advanced to patients much more rapidly than traditional drug discovery and development approaches, offering hope to GIST patients whose disease progresses rapidly without treatment as well as patients whose cancer becomes resistant to current therapy. This project will define not only a path for drug repurposing and rediscovery but also define roles the collaborating CTSA centers can play in assisting others within the consortium. The competencies established and enhanced through this collaboration are synergistic with, and assist in advancing competencies and capabilities established through the CTSA program, notably the CTSA Pharmaceutical Assets Portal. Although this project focuses on a rare gastrointestinal cancer, the approach outlined in this application is applicable across a broad range of therapeutic areas, is scalable within the CTSA consortium, and can be replicated at other CTSA centers.